Maternal cigarette smoking is a major public health problem in the United States. Overall, approximately 20% of women in the US are regular cigarette smokers. Only 30% of US women who abuse tobacco quit smoking when they find out they are pregnant. Epidemiological studies indicate that children of mothers who smoke -10 cigarettes a day throughout gestation exhibit increased vulnerability for substance abuse disorder. Currently, little is known about the neurobehavioral mechanisms through which prenatal nicotine (NIC) exposure renders offspring of maternal smokers more vulnerable to substance abuse. The proposed program of research will test the hypothesis that repeated, prenatal IV NIC will alter normal mesocorticolimbic DA function during gestation, thereby altering the locomotor, reinforcing, and rewarding effects of METH or COC in adulthood. The proposed mechanism of subsequent psychostimulant-induced behavioral alterations is dopaminergic. First, the dose dependent effects of prenatal NIC on the induction, and expression, of intravenous (IV) methamphetamine (METH) or cocaine (COC)-induced behavioral sensitization in adult female and male rats will be determined. We have found that maternal smoke exposure (putatively NIC) produced increased COC-induced hyperactivity in female offspring. Second, we will determine the changes in DA receptors and DA transporters in adult male and female rats prenatally exposed to NIC and behaviorally sensitized to IV METH or COC to establish a mechanism of action. Third, the effects of prenatal NIC on the relative reinforcement and reward produced by IV METH or COC in adult female and male rats will be determined. The long-term programmatic goal of the present research proposal is to elucidate the neurobiological mechanisms that render people exposed to in utero NIC more vulnerable to substance abuse. The IV model of prenatal NIC exposure, in combination with contemporary methods to assess drug related behaviors, is innovative and will be translational to the health issues of drug abuse and the neurological complications that result from maternal smoking. The ultimate goal of this research is to develop drug prevention strategies and pharmacotherapies to decrease vulnerability to drug abuse.